Steatohepatitis (also known as fatty liver disease) is a type of liver disease, characterized by liver inflammation with concurrent fat accumulation in the liver. Classically seen in alcoholics as part of alcoholic liver disease, steatohepatitis is also frequently found in people with diabetes and obesity and is related to metabolic syndrome.
When not associated with excessive alcohol intake, it is referred to as non-alcoholic steatohepatitis (also known as “NASH”), and is the progressive form of the relatively benign non-alcoholic fatty liver disease. Steatohepatitis of either etiology may progress to cirrhosis, and NASH is now believed to be a frequent cause of unexplained cirrhosis. NASH is also associated with lysosomal acid lipase deficiency.
Steatohepatitis is characterized microscopically by hepatic fat accumulation (steatosis), mixed lobular inflammation, ballooning degeneration of hepatocytes (sometimes with identifiable Mallory bodies), glycogenated hepatocyte nuclei, and pericellular fibrosis. The “chicken wire” pattern of the pericellular fibrosis, which affects portal areas only secondarily in later stages, is very characteristic and is identified on trichrome stains.
NASH is commonly associated with metabolic syndrome (obesity, dyslipidemia and insulin resistance). Further progression of the disease is probably caused by chronic inflammation and reactive oxygen species formation. Metabolically induced liver inflammation recruits additional inflammatory components (neutrophils, AP-1 pathway) and causes NASH. A retrospective cohort study concluded that liver failure is the main cause of morbidity and mortality in NASH-associated cirrhosis. No treatment has yet emerged as the “gold standard” for NASH.
Digoxin is a purified cardiac glycoside similar to digitoxin extracted from the foxglove plant, Digitalis lanata. Digoxin is widely used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication. In such diseases, high ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the atrioventricular (AV) node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves owing to improved filling.
Digoxin is a cardiac glycoside that acts as an inotropic agent; it decreases the action of the Na+/K+ ATPase channel by binding to an allosteric site. Normally 3×Na+ move out of the cardiac cell, and 2×K+ move into the cardiac cell. As a result, Na+ concentration in myocyte increases and inactivates the NCX antiporter protein, wherein Na+ is no longer be pumped into the myocyte. On the other hand, inactivation of NCX causes Ca2+ concentration to increase inside the cell, as Ca2+ cannot be pumped out. Increase in Ca2+ concentration thus aid contraction in the heart. Digoxin also acts as a vagal agonist, with a secondary effect of decreased heart rate. Digoxin toxicity is marked by atrial tachycardia (due to ectopy) and AV block (due to its vagal stimulating properties). Digoxin further reduces the risk of certain kinds of cancer, but not at the therapeutic concentrations used to treat cardiac diseases.
There is a need in the art to identify novel therapeutic treatments that can be used to treat or prevent non-alcoholic steatohepatitis (also known as NASH) in a mammal. There is also a need in the art to identify novel therapeutic treatments that can be used to treat or prevent other liver diseases or disorders, such as, but not limited to, liver injury associated with and/or caused by alcohol consumption in a mammal afflicted with NASH, alcoholic hepatitis, drug induced liver injury, primary sclerosing cholangitis, viral hepatitis, liver fibrosis, liver cirrhosis, and/or other toxic liver conditions in a mammal. There is also a need in the art to identify novel therapeutic treatments that can be used to treat or prevent promote weight loss in a mammal. The present invention addresses and meets these needs.